Small molecule fights dengue in mice

There are about 96 million symptomatic cases of dengue each year, according to the World Health Organization. People with the virus, which is transmitted through mosquito bites, experience fever, rashes, and joint pain. In serious cases it can be life-threatening. No drug exists to prevent or treat dengue virus, but scientists now report a small molecule called JNJ-A07 that can kill all four types of dengue virus in cells. The compound also is effective at fighting dengue in mice (Nature 2021, DOI: 10.1038/s41586-021-03990-6).

Scientists led by Johan Neyts of KU Leuven, Patrick Chaltin of CD3, and Marnix Van Loock of Janssen Pharmaceutica, a subsidiary of Johnson & Johnson, developed the compound. JNJ-A07 prevents dengue virus from making copies of itself by blocking the interaction of two viral proteins—NS3 and NS4B. This mechanism of action has not been used by drugmakers before. Earlier this year, scientists at the Novartis Institute for Tropical Diseases reported a dengue antiviral called NITD-688 that also interacts with NS4B via a different mechanism (Sci. Trans. Med. 2021, DOI: 10.1126/scitranslmed.abb2181).

Although tests in cells showed that dengue virus developed resistance to JNJ-A07, that process took at least 25 weeks, and the mutant viruses that emerged were not able to copy themselves in mosquito cells. The researchers say both those factors indicate that resistance is unlikely to be a problem with JNJ-A07.

“A drug for treatment and prophylaxis of dengue fever may be within reach,” Christoph Nitsche says in an email. Nitsche, who studies dengue virus therapies at the Australian National University, adds that he hopes future studies will show how NSB4 inhibitors interact with the protein.

The researchers are developing an analog of JNJ-A07, which they will discuss at the American Society of Tropical Medicine and Hygiene annual meeting in November.